In year 1, we have studied regional brain metabolic activity of 17 depressed unipolar patients and 15 normal controls and 2 anxious patients with positron emission tomography (PET) scans before and after a night of sleep deprivation (SD). We found that a third of our depressed unipolar patients responded to sleep deprivation. The depressed responders have higher activity of the limbic system (specifically of the cingulate cortex) than the depressed nonresponders or the normal controls. The depressed responders also showed a much larger decrease in activity in these brain systems after sleep deprivation whereas the depressed nonresponders showed no such decrease. We believe that the increased activity of the cingulate cortex in the depressed responders may reflect a cholinergic hyperactivity. We propose a model in which decreases in SWS and REM latency in depressed patients are associated with a dysregulation of metabolic homeostasis characterized by the failure to show the normal drop in core body temperature with sleep and by abnormal elevations in regional brain metabolism, which is temporarily reversed with SD. In years 3-5, we plan on studying 60 depressed patients with PET scans before and after sleep deprivation and after recovery night sleep. We anticipate approximately 20 of the patients will show a significant improvement with sleep deprivation. We hypothesize that brain activity in the cingulate cortex will increase in responders who relapse after recover night sleep. We also plan on studying 30 additional depressed patients before and after early or late partial sleep deprivation (PSD). We hypothesize that late PSD will result in a greater reduction of regional brain activity than early PSD. A cohort of depressed patients will enter a randomly assigned, double blind placebo controlled lithium trial to be started before sleep deprivation. We plan on studying an additional cohort of depressed patients with PET scans before and after sleep deprivation and again after a four week trial of fluoxeline.